Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities

Ilona Cuijpers; Steven J. Simmonds; Marc van Bilsen; Elibieta Czarnowska; Arantxa Gonzalez Miqueo; Stephane Heymans; Annika R. Kuhn; Paul Mulder; Anna Ratajska; Elizabeth A. Jones; Ebba Brakenhielm

doi:10.1007/s00395-020-0798-y

Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities

Ilona Cuijpers, Steven J. Simmonds, Marc van Bilsen, Elibieta Czarnowska, Arantxa Gonzalez Miqueo, Stephane Heymans, Annika R. Kuhn, Paul Mulder, Anna Ratajska, Elizabeth A. Jones^*, Ebba Brakenhielm^*

^*Corresponding author for this work

Research output: Contribution to journal › (Systematic) Review article › peer-review

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.

Original language	English
Article number	39
Number of pages	15
Journal	Basic Research in Cardiology
Volume	115
Issue number	4
DOIs	https://doi.org/10.1007/s00395-020-0798-y
Publication status	Published - 25 May 2020

Keywords

Heart failure with preserved ejection fraction
Coronary microvascular dysfunction
Cardiac lymphatic dysfunction
Inflammation
Myocardial fibrosis
Cardiac metabolism
PRESERVED EJECTION FRACTION
VENTRICULAR DIASTOLIC DYSFUNCTION
MYOCARDIAL SUBSTRATE METABOLISM
OBSTRUCTIVE PULMONARY-DISEASE
OXIDE SYNTHASE EXPRESSION
ENDOTHELIAL GROWTH-FACTOR
HEART-FAILURE
VASCULAR-PERMEABILITY
OXIDATIVE STRESS
CARDIAC LYMPHANGIOGENESIS

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@article{57a16a3bc66e4d29bff55b493ec23ba8,

title = "Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities",

abstract = "Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.",

keywords = "Heart failure with preserved ejection fraction, Coronary microvascular dysfunction, Cardiac lymphatic dysfunction, Inflammation, Myocardial fibrosis, Cardiac metabolism, PRESERVED EJECTION FRACTION, VENTRICULAR DIASTOLIC DYSFUNCTION, MYOCARDIAL SUBSTRATE METABOLISM, OBSTRUCTIVE PULMONARY-DISEASE, OXIDE SYNTHASE EXPRESSION, ENDOTHELIAL GROWTH-FACTOR, HEART-FAILURE, VASCULAR-PERMEABILITY, OXIDATIVE STRESS, CARDIAC LYMPHANGIOGENESIS",

author = "Ilona Cuijpers and Simmonds, {Steven J.} and {van Bilsen}, Marc and Elibieta Czarnowska and Miqueo, {Arantxa Gonzalez} and Stephane Heymans and Kuhn, {Annika R.} and Paul Mulder and Anna Ratajska and Jones, {Elizabeth A.} and Ebba Brakenhielm",

note = "Funding Information: This work was supported by an European Research Area Network Cardiovascular disease [LYMIT-DIS 2016] consisting of funding from Fonds Wetenschappelijk Onderzoek [GOH7716N to E.A.V.J.], Agence National de la Recherche [16-ECVD-0004 to E.B. and P.M.], Nederlandse organisatie voor Wetenschappelijk Onderzoek [ZonMw 2016T091 to M.v.B.], and Instituto de Salud Carlos III [AC16/00020 to A.G.], National Centre for Research and Development [ERA-CVD/LyMitDis/1/2017 to A.R. and E.C.]. I.C. and A.G. were supported by the Fonds Wetenschappelijk Onderzoek [1160718N] and the Instituto de Salud Carlos III [CB16/11/00483 and PI18/01469], respectively. E.A.V.J., S.H., and S.J.S. were supported by Fonds Wetenschappelijk Onderzoek [G091018N]. S.H. acknowledges the support of the European Research Area Network Cardiovascular disease [Macro ERA 2016], Nederlandse organisatie voor Wetenschappelijk Onderzoek [Vidi 91796338], Dutch Heart Foundation [CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, Grant 2017-21, and Arena-PRIME, 2017-18]. E.B. and P.M. acknowledge the support of the FHU REMOD-VHF and generalized institutional funds from INSERM, and the European Regional Development Fund [CPER/FEDER 2015 (DO-IT) and CPER/FEDER 2016 (PACT-CBS)]. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = may,

day = "25",

doi = "10.1007/s00395-020-0798-y",

language = "English",

volume = "115",

journal = "Basic Research in Cardiology",

issn = "0300-8428",

publisher = "Springer",

number = "4",

}

TY - JOUR

T1 - Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities

AU - Cuijpers, Ilona

AU - Simmonds, Steven J.

AU - van Bilsen, Marc

AU - Czarnowska, Elibieta

AU - Miqueo, Arantxa Gonzalez

AU - Heymans, Stephane

AU - Kuhn, Annika R.

AU - Mulder, Paul

AU - Ratajska, Anna

AU - Jones, Elizabeth A.

AU - Brakenhielm, Ebba

N1 - Funding Information: This work was supported by an European Research Area Network Cardiovascular disease [LYMIT-DIS 2016] consisting of funding from Fonds Wetenschappelijk Onderzoek [GOH7716N to E.A.V.J.], Agence National de la Recherche [16-ECVD-0004 to E.B. and P.M.], Nederlandse organisatie voor Wetenschappelijk Onderzoek [ZonMw 2016T091 to M.v.B.], and Instituto de Salud Carlos III [AC16/00020 to A.G.], National Centre for Research and Development [ERA-CVD/LyMitDis/1/2017 to A.R. and E.C.]. I.C. and A.G. were supported by the Fonds Wetenschappelijk Onderzoek [1160718N] and the Instituto de Salud Carlos III [CB16/11/00483 and PI18/01469], respectively. E.A.V.J., S.H., and S.J.S. were supported by Fonds Wetenschappelijk Onderzoek [G091018N]. S.H. acknowledges the support of the European Research Area Network Cardiovascular disease [Macro ERA 2016], Nederlandse organisatie voor Wetenschappelijk Onderzoek [Vidi 91796338], Dutch Heart Foundation [CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, Grant 2017-21, and Arena-PRIME, 2017-18]. E.B. and P.M. acknowledge the support of the FHU REMOD-VHF and generalized institutional funds from INSERM, and the European Regional Development Fund [CPER/FEDER 2015 (DO-IT) and CPER/FEDER 2016 (PACT-CBS)]. Publisher Copyright: © 2020, The Author(s).

PY - 2020/5/25

Y1 - 2020/5/25

N2 - Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.

AB - Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.

KW - Heart failure with preserved ejection fraction

KW - Coronary microvascular dysfunction

KW - Cardiac lymphatic dysfunction

KW - Inflammation

KW - Myocardial fibrosis

KW - Cardiac metabolism

KW - PRESERVED EJECTION FRACTION

KW - VENTRICULAR DIASTOLIC DYSFUNCTION

KW - MYOCARDIAL SUBSTRATE METABOLISM

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - OXIDE SYNTHASE EXPRESSION

KW - ENDOTHELIAL GROWTH-FACTOR

KW - HEART-FAILURE

KW - VASCULAR-PERMEABILITY

KW - OXIDATIVE STRESS

KW - CARDIAC LYMPHANGIOGENESIS

U2 - 10.1007/s00395-020-0798-y

DO - 10.1007/s00395-020-0798-y

M3 - (Systematic) Review article

C2 - 32451732

SN - 0300-8428

VL - 115

JO - Basic Research in Cardiology

JF - Basic Research in Cardiology

IS - 4

M1 - 39

ER -

Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities

Abstract

Keywords

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